15-deoxyprostaglandin-j2 and Carcinoma--Hepatocellular

Microsomal prostaglandin E synthase 1 (mPGES-1) is the terminal regulator of PGE₂ synthesis. The expression of mPGES-1 is increased by stimulating inflammatory factors in various human cancers. However, whether hepatitis B virus (HBV) infection affects mPGES-1 and its molecular mechanism in liver cells has not been studied. In this study, we observed that mPGES-1 expression was positively correlated with HBV X protein (HBx) in hepatocellular carcinoma cancerous tissue, and HBx enhanced the mPGES-1 promoter activity in HL7702 liver cells. Mechanistic investigations revealed that HBx can increase the early growth response 1 (EGR1) binding to the transcription site of mPGES-1 promoter. The overexpression and knockdown of EGR1 did not affect cyclooxygenase-2 (COX-2) transcription and expression in HL7702-HBx cells. We also investigated the unique function of 15-deoxy-Δ(12,14)-prostaglandin J₂ (15d-PGJ₂), a kind of PGE₂ inhibitor, in the regulation of mPGES-1 expression in HBx-positive liver cells. In the presence of 15d-PGJ₂, the expression of COX-2 was unaffected, but that of the EGR1-mPGES-1-PGE₂ axis was inhibited. Moreover, the capacity of EGR1 binding to the mPGES-1 promoter decreased, and the change in HL7702-HBx cells was more significant. The results indicated that EGR1 is a specific transcription factor in the up-regulation of mPGES-1 expression by HBx, and targeting EGR1 may contribute to inhibiting the change from inflammation to HBV-induced cancer.

Topics: Base Sequence; Binding Sites; Carcinoma, Hepatocellular; Cyclooxygenase 2; Dinoprostone; Early Growth Response Protein 1; Female; Gene Expression Regulation; Hepatitis B virus; Humans; Intramolecular Oxidoreductases; Liver Neoplasms; Male; Middle Aged; Molecular Sequence Data; Promoter Regions, Genetic; Prostaglandin D2; Prostaglandin-E Synthases; Trans-Activators; Up-Regulation; Viral Regulatory and Accessory Proteins

Emerging evidence suggests that tumor-initiating cells (TICs) are the most malignant cell subpopulation in tumors because of their resistance to chemotherapy or radiation treatment. Targeting TICs may be a key innovation for cancer treatment. In this study, we found that PPARγ agonists inhibited the cancer stem cell-like phenotype and attenuated tumor growth of human hepatocellular carcinoma (HCC) cells. Reactive oxygen species (ROS) initiated by NOX2 upregulation were partially responsible for the inhibitory effects mediated by PPARγ agonists. However, PPARγ agonist-mediated ROS production significantly activated AKT, which in turn promoted TIC survival by limiting ROS generation. Inhibition of AKT, by either pharmacological inhibitors or AKT siRNA, significantly enhanced PPARγ agonist-mediated inhibition of cell proliferation and stem cell-like properties in HCC cells. Importantly, in nude mice inoculated with HCC Huh7 cells, we demonstrated a synergistic inhibitory effect of the PPARγ agonist rosiglitazone and the AKT inhibitor triciribine on tumor growth. In conclusion, we observed a negative feedback loop between oxidative stress and AKT hyperactivation in PPARγ agonist-mediated suppressive effects on HCCs. Combinatory application of an AKT inhibitor and a PPARγ agonist may provide a new strategy for inhibition of stem cell-like properties in HCCs and treatment of liver cancer.

Topics: AC133 Antigen; Animals; Antigens, CD; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Enzyme Activation; Glycoproteins; Humans; Liver Neoplasms; Male; Membrane Glycoproteins; Mice; Mice, Nude; NADPH Oxidase 2; NADPH Oxidases; Neoplastic Stem Cells; Oxidative Stress; Peptides; Phenotype; PPAR gamma; Prostaglandin D2; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Ribonucleosides; Rosiglitazone; Thiazolidinediones